Schizophrenia is a common psychotic disorder with peak incidence in early adulthood that often leads to lifelong morbidity. Several candidate genes for schizophrenia have been replicated in independent samples;each accounts for only a small increase in risk for an individual, and taken together they account for only a small percentage of the overall population risk of schizophrenia. Thus, identification of additional risk genes is crucial. In this revised application, we propose to identify the genetic variation located in chromosomal region 5q31-35 that leads to increased susceptibility to schizophrenia. Linkage to this region has been detected in multiple populations and thus identification of a candidate gene for association with schizophrenia is likely to identify a general risk factor. Prior to detailed haplotype mapping, a three-pronged approach to narrow the locus will be taken that includes detailed genealogy, joint linkage analysis with other investigators, and fine mapping in families with many affected members. Within the narrowed region, we will then commence screening association studies initially focusing on strong biological candidate genes in the 5q locus. Individual SNPs and haplotypes will be tested for association with schizophrenia in a sample of Portuguese schizophrenia patients (n=631 affecteds). Nominally positive results will be followed up in a large replication sample that is a collaboration between four academic centers (n=3,545 DNAs). Further testing of the linked region will occur in the Azorean samples by an interval-based approach with novel sliding window statistical analyses. In order to determine the interactions between the chromosome 5 locus and other loci, haplotype maps will be created for genes previously implicated in schizophrenia. Individual haplotypes in these genes will be tested for association in the screening sample and for gene-gene interactions with any gene identified on chromosome 5q. In depth phenotypic investigation by latent class analysis will be coupled with the haplotype analyses to identify subgroups of schizophrenia. We expect these studies to be significant in that they will identify a common risk factor for schizophrenia and help elucidate its role in schizophrenia risk.